HIV and AIDs I Flashcards
Characterized by immunodeficiency resulting from loss of CD4+ T lymphocytes, and development of lifethreatening opportunistic infections
AIDs
One of the most prevalent places of HIV infection in the world is
Africa south of the sahara
In infected persons, infectious quantities of HIV (and infected cells, also infectious) are present in blood, CSF, and semen, with smaller quantities in
Vaginal secretions and milk
Spread by parenteral exposure to blood, sexual intercourse, perinatally, and rarely from other forms of contact
HIV
Before testing was available, many people were infected with HIV via
Transfusions
Increase the risk of transmission, by damaging mucosal barriers and locally increasing the number of white blood cells which may become infected
Genital tract infections or injuries
Present in human seminal plasma was found to increase infectivity of virions by many orders of magnitude, making this interaction an attractive potential target for drug development
Prostatic acid phosphatase fragment
The decline in deths from AIDs after 1995 reflects the development of a
Highly-Active Anti-Retroviral Therapy (HAART)
The use of a combination of two RT inhibitors plus a protease inhibitor
HAART
The biology of HIV is deeply intertwined with the biology of its
Host cells
HIV gene products replicate its genome and form the structural components of
New Virions
A recent survey identified over 250 host-cell proteins required for efficient
HIV replication
Cytosolic contents are wrapped in a double shell of membrane and delivered to endosomes in
Autophagy
Normally function in formation of multi-vesicular bodies and degradation of plasma membrane proteins, are required for budding of HIV virions
Proteins of the ESCRT complexes (Endosomal Sorting Complexes Required for Transport)
The primary receptor for HIV is
CD4
The cell tropism of HIV is largely determined by the distribution of
CD4
A plasma membrane glycoprotein that in structure resembles an immunoglobulin heavy chain, with four immunoglobulin-type domains
CD4
CD4 is present on helper T cells and cells of the monocyte/macrophage lineage, including dendritic cells of epithelia, which may be the initial cells infected with
Sexually transmitted HIV
HIV binding to dendritic cells may also facilitate infection of
T cells
A surface protein of dendritic cells that binds HIV virions to the cell surface
DC-SIGN
Attract T cells, which then become infected
Dendritic cell chemokines
After infection macrophages can spread HIV, especially to secondary lymphoid organs and the
Brain
Can block HIV infection by occupying the receptor
Chemokine receptors
About 1% of U.S. Caucasians (and a lower faction of Black and Hispanic Americans) are homozygous for a deletion in the gene for the receptor
CCR5
Such persons have slower progression of disease after infection. However, they eventually develop
AIDS
The number of CCR5 gene copies varies between individuals - the higher the copy number the more rapid the progression to
AIDs
Some CD4- cells can be infected with HIV in vivo, especially brain astrocytes and oligodendrocytes and epithelial cells of the
Bowel
Here, the receptor may be a
Glycolipid, galactosyl ceramide
The ability of HIV to establish productive infection depends on the state of the cell infected. Monocytes and resting T cells produce little if any
Virus
However, these support abundant virus replication
Macrophages and activated T cells
The state of the infected cell may affect reverse transcription, integration, or
Virus transcription
The HIV promoter binds numerous cellular transcription factors (notably NF-KB) which are activated when T cells are stimulated by cytokines such as
TNF
Thus, T cells can not be stimulted to fight HIV without also stimulating its
Replication
Infection by HIV can result in a state of
-The provirus is integrated into the host genome but not expressed
True viral latency
Such cells persist in the face of an immune response because they produce no viral antigens and, since there is no viral replication, latent HIV is not sensitive to
Anti-viral agents
Latently-infected cells may later become activated and produce
Virus
HIV and other lentiviruses encode six small proteins not produced by other
Retroviruses
Bind to proteinubiquitin ligases, recruit specific host-cell proteins for ubiquitinylation, and promote their destruction by the proteosome
Vif, vpr, and vpu
What are the 6 regulatory proteins?
Tat, rev, nef, vif, vpu, and vpr
Powerful stimulator (100x) of transcription from the HIV promoter
Transactivator (tat)
Inhibits splicing of viral transcripts
Rev
Named for a putative ‘negative effect’
-Actually stimulates HIV replication and may be responsible for damage to the immune system
Nef
Persons infected with nef-defective HIV are ‘slow-progressors’ to
AIDs
Present in virion, required for infectivity
Virion Inefectivity Factor (vif)
Causes degradation of a DNA cytosine deaminase APOBEC which produces mutagenic damage to reverse transcripts
Vif
Stimulates virus release from the cell surface by delivering CD4 to the proteosome, and reducing cellsurface tetherin
Vpu
A protein that binds virions to the cell surface and promotes their endocytosis
Tetherin
Present in virion, may aid in transport of the viral core to nucleus; blocks cell division cycle in G2, when HIV transcription is more efficient than in G1
Vpr
Tat is an activator of
HIV transcription
Binds not to the HIV promoter but to tar (tat response element) of the transcript, which forms a stem-loop structure
Tat
Tar-bound tat binds cellular proteins which stimulate
Transcription
One is a protein kinase which phosphorylates the C-terminal domain of
-Facilitates promoter clearance and rapid transcription
RNA polymerase
Rev prevents splicing of HIV mRNA by binding to
Rev Response Element (RRE) and exportins
Proteins which transport molecules out of the nucleus
Exportins
Early after infection, Rev levels are low and most viral transcripts are fully spliced, so that the small regulatory proteins are
Translated
As Rev accumulates, splicing is blocked, and unspliced and singly-spliced transcripts are able to leave the
Nucleus
Nef-defective Simian AIDS virus (SIV) failed to produce disease and in fact gave rise to a
Protective immune response
Expression of Nef in transgenic mice produces an
AIDS-like syndrome
This suggests that nef may play a key role in
AIDS pathology
Has an attached fatty acid and is bound to the plasma membrane, where it may alter intracellular signaling from membrane receptors and so alter transcription
Mature Nef
Down-regulates expression of CD4, MHC antigens, and cytokines, including IL-2 and IFN-γ
Nef
Induces macrophages to secrete soluble factors which up-regulate proteins on resting T cells, causing them to become susceptible to HIV infection
Nef
A cellular defense against retroviruses is
APOBEC
A deaminase that converts cytosine to uracil in viral DNA, creating mutations
APOBEC
The deaminase is incorporated into new virions and acts on the DNA strands produced by
Reverse transcription
Incorporated into HIV virions and excludes the deaminase APOBEC
Wif
One member of this protein family produces an intestine-specific form of Apo-B shorter than the liver form, by converting a cytosine in mRNA to uracil and creating a stop codon
Vif
Another member of the Vif family causes hypermutation of
Ig-gene
A host protein used by HIV to defend itself
Cyclophilin
Cyclophilin was named because it binds the immunosuppressant
Cyclosporin A
Mammalian cells contain ‘restriction factors’, proteins which bind CA proteins of infecting virions and block
Virus Replication
Binds Cyclophilin; it is incorporated into virions and, in an as-yet-unknown way, blocks a ‘restriction factor’
HIV CA
Typically follows exposure to HIV by 4-8 weeks. Symptoms are non-specific and may include (from most to least common) fever, lymphadenopathy, rash, pharyngitis, myalgia, diarrhea, headache, nausea, hepatosplenomegaly, peripheral- or CNS symptoms
Acute HIV infection
Acute HIV infection typically presents how long after initial infection?
4-8 Weeks
In acute disease there is rapid viral replication and high-level
Viremia
Can be found in the blood during acute HIV infection?
Infectious virus and CA (p24) antigen
After a few weeks, HIV-specific CTL appear and a strong cell-mediated immune response clears virus from the
Bloodstream
Anti-HIV antibodies (seroconversion) may not appear until
2-6 Months after infection
Gut lymphoid tissue is a major site of early
HIV replication
Massive early loss of T cells creates “holes” in the T-cell repertoire as clones of memory cells are eliminated by the
Virus
T cells with anti-HIV specificity may be especially susceptible to
Infection and killing
Binds integrin α4β7
HIV SU protein
The receptor which causes memory T cells to ‘home’ to mucosal lymphoid tissue
Integrin α4β7
This in turn up-regulates the membrane protein
LFA-1
Promotes cell-cell association of T cells and may promote cell-to-cell spread of HIV
LFA-1
Untreated, the median interval between seroconversion and development of AIDS is
10.5 years
This period is known as the
Asymptomatic period
Patients do not feel ill, and unless diagnosed, do not curtail activities that transmit the virus to others
Asymptomatic period
During the asymptomatic period, plasma viremia is typically low due to production of
Anti-HIV antibodies
During the asymptomatic period, dendritic cells trap these immune complexes and remove virus from the circulation; however this may facilitate infection of dendritic cells and/or transfer of virus to
T cells
Plasma virus load determines the speed of progression to
Symptomatic disease
Which cell type has the longest half-life when treated with HIV drugs?
Infected macrophages and dendritic cells
During the ‘asymptomatic period’ there is slow but steady alteration of the
Immune system
Early there is B-cell dysregulation, polyclonal B-cell proliferation, and proliferation of
CD8 T cells
Later, although the total concentration of circulating lymphocytes does not change, the ratio of CD4+ to CD8+ cells progressively
Declines
Within the TH population, we see an
Increase in TH2 cells and decrease in TH1 cells
T-cell proliferation and CMI are compromised and may ultimately lead to failure of the anti-HIV
CTL response
Response of T-cells to previously-encountered antigens also declines, perhaps because HIV preferentially infects
Memory T cells
Lymphadenopathy, fever, weight loss, persistent diarrhea, and Candida infection (the “AIDS-related” complex or ARC), are the initial manifestations of
Immune-system failure?
Defined by rapid decline of CD4+ lymphocytes, rapid increase in plasma viremia, and development of opportunistic infections
-The last stage of HIV disease
AIDS
